Antiviral benzimidazole nucleoside analogues and a method for their preparation

ABSTRACT

The present invention relates to benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to the preparation of the benzimidazole derivatives and pharmaceutical formulations containing them.

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/GB95/01597 filed Jul. 6, 1995 which claims priority from GB9413724.7 filed Jul. 7, 1994.

The present invention relates to benzimidazole derivatives and their usein medical therapy particularly for the treatment or prophylaxis ofvirus infections such as those caused by herpes viruses. The inventionalso relates to the preparation of the benzimidazole derivatives andpharmaceutical formulations containing them.

Of the DNA viruses, those of the herpes group are the sources of themost common viral illnesses in man. The group includes herpes simplexvirus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus(CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6) andhuman herpes virus type 7 (HHV-7). HSV-1 and HSV-2 are some of the mostcommon infectious agents of man. Most of these viruses are able topersist in the host's neural cells; once infected, individuals are atrisk of recurrent clinical manifestations of infection which can be bothphysically and psychologically distressing.

HSV infection is often characterised by extensive and debilitatinglesions of the skin, mouth and/or genitals. Primary infections may besubclinical although tend to be more severe than infections inindividuals previously exposed to the virus. Ocular infection by HSV canlead to keratitis or cataracts thereby endangering the host's sight.Infection in the new-born, in immnunocompromised patients or penetrationof the infection into the central nervous system can prove fatal.

VZV is a herpes virus which causes chickenpox and shingles. Chickenpoxis the primary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

In common with other herpes viruses, infection with CMV leads to alifelong association of virus and host. Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases.

The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin β-cell lymphoma, thymomas andoral hairy leukoplakia. EBV infections have also been found inassociation with a variety of epithelial-cell-derived tumours of theupper and lower respiratory tracts including the lung.

HHV-6 has been shown to be a causative agent of infantum subitum inchildren and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

PCT Patent Specification Nos. WO 92/07867 and WO 94/08456 describecertain antiviral polysubstituted benzimidazole nucleoside analoguesincluding β-D-ribofuranosyl riboside analogues. PCT Patent SpecificationNo. WO 93/18009 describes certain antiviral benzimidazole analogues inwhich the sugar residue is replaced by a carbocyclic group.

It has now been discovered that certain L-sugar substitutedbenzimidazole compounds as referred to below, are useful for thetreatment or prophylaxis of certain viral infections. According to afirst aspect of the present invention, novel compounds of the formula(I) are provided: ##STR1## wherein R represents hydrogen, a halo atom,--NR¹ R² where R¹ and R², which may be the same or different, are eachindependently selected from hydrogen, C₁₋₆ alkyl, cyano C₁₋₆ alkyl,hydroxyC₁₋₆ alkyl, haloC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkylC₃₋₇cycloalkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₂₋₆ alkynyl, aryl,arylC₁₋₆ alkyl, heterocyclicC₁₋₆ alkyl, --COC₁₋₆ alkyl or R¹ R² togetherwith the N atom to which they are attached form a 3, 4, 5 or 6 memberedheterocyclic ring and pharmaceutically acceptable derivatives thereof.

A further suitable group of compounds of formula (I) is that of formula(Ia) ##STR2## wherein R represents hydrogen or --NR¹ R², which may bethe same or different, are each independently selected from hydrogen,C₁₋₆ alkyl, cyanoC₁₋₆ alkyl, hydroxyC₁₋₆ alkyl, haloC₁₋₆ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,arylC₁₋₆ alkyl, heterocyclicC₁₋₆ alkyl, --COC₁₋₆ alkyl (provided that R¹R² are not both hydrogen) or R¹ R² together with the N atom to whichthey are attached form a 3, 4, 5 or 6 membered heterocyclic ring andpharmaceutically acceptable derivatives thereof.

Examples of compounds of formula (I) include the following β anomers offormula (Ib) ##STR3## wherein R represents a halo atom or --NR¹ R²wherein R¹ represents hydrogen and R² is selected from C₁₋₆ alkyl,hydroxyC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkyl C₃₋₇ cycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, arylalkyl, or R¹ and R², which may be thesame or different, are both C₁₋₆ alkyl, or R¹ R² together with the Natom to which they are attached form a 3, 4, 5 or 6 memberedheterocyclic ring and pharmaceutically acceptable derivatives thereof.

In the alternative, compounds of formula (Ib) are compounds wherein Rrepresents a halo atom or a monoC₁₋₆ alkylamino, mono(C₁₋₆hydroxyalkyl)amino, di-C₁₋₆ alkylamino, C₃₋₇ cycloalkylamino, C₁₋₆alkyl-C₃₋₇ cycloalkylamino, C₂₋₆ alkenylamino, C₂₋₆ alkynylamino,arylamino, arylalkylamino, or a group of formula --N(CH₂)_(n), wherein nis 2, 3, 4 or 5 and pharmaceutically acceptable derivatives thereof.

Further examples of compounds of formula (I) above include Examples 1 to38 as described hereinafter

As used herein the term alkyl as a group or part of a group means astraight or branched chain alkyl group. Such alkyl groups preferablyhave 1-6 carbon atoms, most preferably 1 to 4 and in particular includemethyl, ethyl, i-propyl, t-butyl. References to alkenyl groups includegroups which may be in the E- or Z- form or a mixture thereof and whichwhen they contain at least three carbon atoms, may be branched. The termhalo includes chloro, bromo, fluoro and iodo. The term haloC₁₋₆ alkylmeans an alkyl group in which one or more hydrogens is replaced by haloand preferably containing one, two or three halo groups. Examples ofsuch groups include trifluoromethyl and fluoroisopropyl. The term arylas a group or part of a group means phenyl optionally substituted withone or more substituents selected from C₁₋₆ alkoxy, (for examplemethoxy), nitro, halogen, (for example chloro), amino, carboxylate andhydroxy. The term heterocyclic means a saturated or partially saturated(i.e. non-aromatic) 3-,4-,5- or 6- membered ring containing one or more(for example one to four) hetero atoms independently selected fromnitrogen, oxygen and sulphur. Examples of such groups includepyrrolidine.

The present invention includes within its scope each possible alpha andbeta anomer of the compounds of formula (I) and their physiologicallyfunctional derivatives, substantially free of the other anomer, that isto say no more than about 5% w/w of the other anomer, preferably no morethan about 2% w/w, in particular less than 1% w/w will be present, andmixtures of such alpha and beta anomers in any proportions. Compounds offormula (I) in the beta anomeric form are preferred.

Preferred compounds of formula (Ib) include those wherein R represents--NR¹ R² wherein R¹ represents hydrogen and R² is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl and haloC₁₋₆ alkyl and pharmaceuticallyacceptable derivatives thereof.

Particularly preferred compounds of formula (Ib) include those wherein Rrepresents isopropylarnino, isobutylamino, sec-butylamino,cyclopropylamino, cyclopentylamino and 2-fluoro-1-methylethylamino andpharmaceutically acceptable derivatives thereof.

Compounds of formula (I) having the beta configuration which are ofspecial interest as antiviral agents are2-cyclopropylamino-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazole,5,6-dichloro-2-((2-fluoro-1-methylethylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoleand 5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazoleand pharmaceutically acceptable derivatives thereof.

The compound5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole hasbeen found to be particularly useful in the treatment of CMV infections.

The compounds of formula (I) including compounds of formula (Ia) and(Ib) above and their pharmaceutically acceptable derivatives arehereinafter referred to as the compounds according to the invention.

By "a pharmaceutically acceptable derivative" is meant anypharmaceutically or pharmacologically acceptable salt, ester or salt ofsuch ester of a compound according to the invention, or any compoundwhich, upon administration to the recipient, is capable of providing(directly or indirectly) a compound according to the invention, or anantivirally active metabolite or residue thereof.

Preferred esters of the compounds according to the invention areindependently selected from the following groups: (1) carboxylic acidesters obtained by esterification of the 2'-, 3'- and/or 5'-hydroxygroups, in which the non-carbonyl moiety of the carboxylic acid portionof the ester grouping is selected from straight or branched chain alkyl(for example, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example,methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (forexample, phenoxymethyl), aryl (for example, phenyl optionallysubstituted by, for example, halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy oramino); (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (forexample, methanesulphonyl); (3) amino acid esters (for example, L-valylor L-isoleucyl); (4) phosphonate esters and (5) mono-, di- ortriphosphate esters. The phosphate esters may be further esterified by,for example, a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di(C₆₋₂₄)acyl glycerol.

In such esters, unless otherwise specified, any alkyl moiety presentadvantageously contains from 1 to 18 carbon atoms, particularly form 1to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Anycycloalkyl moiety present in such esters advantageously contains from 3to 6 carbon atoms. Any aryl moiety present in such esters advantageouslycomprises a phenyl group.

Preferred carboxylic acid esters according to the present inventioninclude the acetate, butyrate and valerate esters. L-valyl is aparticularly preferred amino acid ester.

Any reference to any of the above compounds also includes a reference toa pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts include salts of organic carboxylicacids such as ascorbic, acetic, citric, lactic, tartaric, malic, maleic,isethionic, lactobionic, p-aminobenzoic and succinic acids; organicsulphonic acids such as methanesulphonic, ethanesulphonic,benzenesulphonic and p-toluenesulphonic acids and inorganic acids suchas hydrochloric, sulphuric, phosphoric, sulphamic and pyrophosphoricacids.

For therapeutic use, salts of the compounds of formula (I) will bepharmaceutically acceptable. However, salts of acids and bases which arenon-pharmaceutically acceptable may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.All salts, whether or not derived from a pharmaceutically acceptableacid or base, are within the scope of the present invention.

Preferred salts include salts formed from hydrochloric, sulphuric,acetic, succinic, citric and ascorbic acids.

In a further aspect of the invention there are provided the compoundsaccording to the invention for use in medical therapy particularly forthe treatment or prophylaxis of viral infections such as herpes viralinfections. Compounds of the invention have been shown to be activeagainst CMV infections, although early results suggest that thesecompounds could also be active against other herpes virus infectionssuch as HSV-1 and -2, HHV 6 and 7, VZV, EBV and HBV infections.

Other viral conditions which may be treated in accordance with theinvention have been discussed in the introduction hereinbefore. Thecompounds of the present invention are particularly suited to thetreatment or prophylaxis of CMV infections and associated conditions.Examples of CMV conditions which may be treated in accordance with theinvention have been discussed in the introduction hereinbefore.

According to another aspect, the present invention provides a method forthe treatment or prevention of the symptoms or effects of a viralinfection in an infected animal, for example, a mammal including ahuman, which comprises treating said animal with a therapeuticallyeffective amount of a compound according to the invention. According toa particular embodiment of this aspect of the invention, the viralinfection is a herpes virus infection, such as CMV, HSV-1, HSV-2, VZV,EBV, HHV6 or HHV7. A further aspect of the invention includes a methodfor the treatment or prevention of the symptoms or effects of an HBVinfection.

The present invention further provides a method for the treatment of aclinical condition in an animal, for example, a mammal including a humanwhich clinical condition includes those which have been discussed in theintroduction hereinbefore, which comprises treating said animal with atherapeutically effective amount of a compound according to theinvention. The present invention also includes a method for thetreatment or prophylaxis of any of the aforementioned infections orconditions.

In yet a further aspect, the present invention provides the use of acompound according to the invention in the manufacture of a medicamentfor the treatment or prophylaxis of any of the above mentioned viralinfections or conditions.

The above compounds according to the invention and theirpharmaceutically acceptable derivatives may be employed in combinationwith other therapeutic agents for the treatment of the above infectionsor conditions. Combination therapies according to the present inventioncomprise the administration of at least one compound of the formula (I)or a pharmaceutically acceptable derivative thereof and at least oneother pharmaceutically active ingredient. The active ingredient(s) andpharmaceutically active agents may be administered simultaneously ineither the same or different pharmaceutical formulations or sequentiallyin any order. The amounts of the active ingredient(s) andpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. Preferably the combination therapy involves theadministration of one compound according to the invention and one of theagents mentioned herein below.

Examples of such further therapeutic agents include agents that areeffective for the treatment of viral infections or associated conditionssuch as (1 alpha, 2 beta, 3alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(-)BHCG, SQ-34514],oxetanocin-G(3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine), acyclicnucleosides (e.g. acyclovir, valaciclovir, famciclovir, ganciclovir,penciclovir), acyclic nucleoside phosphonates (e.g.(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMC),ribonucleotide reductase inhibitors such as 2-acetylpyridine5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydra-zone,3'-azido-3'-deoxythymidine, other 2',3'-dideoxynucleosides such as2',3'-dideoxycytidine, 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine,2',3'-didehydrothymidine, protease inhibitors such asN-tert-butyl-dehydro-2-[-2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparginyl]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide(Ro 31-8959), oxathiolane nucleoside analogues such as(-)cis-1-(2-hydroxymethyl)-1,3-oxathiolan-5-yl)-cytosine (3TC) orcis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluoro-cytosine (FTC),3'-deoxy-3'-fluorothymidine, 5-chloro-2',3-dideoxy-3-fluorouridine,(-)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol,ribavirin, 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), tatinhibitors such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one(Ro5-3335), or7-chloro-1,3-dihydro-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine(Ro24-7429), interferons such as α-interferon, renal excretioninhibitors such as probenecid, nucleoside transport inhibitors such asdipyridarnole; pentoxifylline, N-Acetylcysteine (NAC), Procysteine,α-trichosanthin, phosphonoformic acid, as well as immunodulators such asinterleukin II or thymosin, granulocyte macrophage colony stimulatingfactors, erythropoetin, soluble CD₄ and genetically engineeredderivatives, thereof, or non-nucleoside reverse transcriptase inhibitorssuch as nevirapine (BI-RG-587), loviride (α-APA) and delavuridine(BHAP), and phosphonoformic acid.

More preferably the combination therapy involves the administration ofone of the above mentioned agents and a compound within one of thepreferred or particularly preferred sub-groups within formula (I) asdescribed above. Most preferably the combination therapy involves thejoint use of one of the above named agents together with one of thecompounds of formula (I) specifically named herein.

The present invention further includes the use of a compound accordingto the invention in the manufacture of a medicament for simultaneous orsequential administration with at least one other therapeutic agent,such as those defined hereinbefore.

The compounds according to the invention, also referred to herein as theactive ingredient, may be administered for therapy by any suitable routeincluding oral, rectal, nasal, topical (including transdermal, buccaland sublingual), vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal and intravitreal). It will beappreciated that the preferred route will vary with the condition andage of the recipient, the nature of the infection and the chosen activeingredient.

In general a suitable dose for each of the above-mentioned conditionswill be in the range of 0.01 to 250 mg per kilogram body weight of therecipient (e.g. a human) per day, preferably in the range of 0.1 to 100mg per kilogram body weight per day and most preferably in the range 0.5to 30 mg per kilogram body weight per day and particularly in the range1.0 to 20 mg per kilogram body weight per day. (Unless otherwiseindicated, all weights of active ingredient are calculated as the parentcompound of formula (I); for salts or esters thereof, the weights wouldbe increased proportionally.) The desired dose may be presented as one,two, three, four, five, six or more sub-doses administered atappropriate intervals throughout the day. In some cases the desired dosemay be given on alternative days. These sub-doses may be administered inunit dosage forms, for example, containing 10 to 1000 mg or 50 to 500mg, preferably 20 to 500 mg, and most preferably 100 to 400 mg of activeingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound from about 0.025 to about100 μM, preferably about 0.1 to 70 μM, most preferably about 0.25 to 50μM. This may be achieved, for example, by the intravenous injection of a0.1 to 5% solution of the active ingredient, optionally in saline, ororally administered as a bolus containing about 0.1 to about 250 mg/kgof the active ingredient. Desirable blood levels may be maintained by acontinuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or byintermittent infusions containing about 0.4 to about 15 mg/kg of theactive ingredient.

While it is possible for the active ingredient to be administered aloneit is preferable to present it as a pharmaceutical formulation. Theformulations of the present invention comprise at least one activeingredient, as defined above, together with one or more acceptablecarriers thereof and optionally other therapeutic agents. Each carriermust be "acceptable" in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient.Formulations include those suitable for oral, rectal, nasal, topical(including transdermal buccal and sublingual), vaginal or parenteral(including subcutaneous, intramuscular, intravenous, intradermal andintravitreal) administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then if necessary shaping the product.

The present invention further includes a pharmaceutical formulation ashereinbefore defined wherein a compound of formula (I) or apharmaceutically acceptable derivative thereof and at least one furthertherapeutic agent are presented separately from one another and as a kitof parts.

Compositions suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain the active compound 1) in an optionally buffered,aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3)dispersed in a polymer. A suitable concentration of the active compoundis about 1% to 25%, preferably about 3% to 15%. As one particularpossibility, the active compound may be delivered from the patch byelectrotransport or iontophoresis as generally described inPharmaceutical Research. 3 (6), 318 (1986).

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g. sodium starchglycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) surface-active or dispersing agent. Moulded tablets may bemade by moulding in a suitable machine a mixture of the powderedcompound moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and may be formulated so as to provideslow or controlled release of the active ingredient therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile. Tablets may optionally be provided with anenteric coating, to provide release in parts of the gut other than thestomach.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavoured basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerine, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Pharmaceutical formulations suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art. The suppositories may beconveniently formed by admixture of the active combination with thesoftened or melted carrier(s) followed by chilling and shaping inmoulds.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multidose sealed containers, for example, ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose orunit, daily sub-dose, as herein above recited, or an appropriatefraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example, those suitable for oral administration mayinclude such further agents as sweeteners, thickeners and flavoringagents.

The present invention further includes the following processes, for thepreparation of compounds of formula (I) above and derivatives thereofwhich comprises:

(A) reacting a compound of formula (II) ##STR4## wherein L is hydrogenand R³, R⁴ and R⁵ are each a hydroxy or a protected hydroxy group, witha suitable halogenating agent such as N-bromosuccinamide or when L is asuitable leaving atom or group, for example, a halo atom such as bromineor an organo (for example alkyl) sulphone, or organo (for example alkylor aralkyl) sulphate such as methylsulphone (MeS(O)₂), methylsulphonate(MeS(O)₂ O) or tosylate (4-MePhS(O)₂ O) group and R³, R⁴ and R⁵ are ashereinbefore defined, with an amine of formula H--NR¹ R² (wherein R¹ andR² are as hereinbefore defined); or

(B) reacting a compound of formula (III) ##STR5## wherein R is ashereinbefore defined, with a compound of formula (IV) ##STR6## whereinR³, R⁴ and R⁵ are each a hydroxy or a protected hydroxy group and L¹ isa suitable leaving group in the α- or β- position, for example, a halo(for example fluoro, chloro or bromo), an alkyl- or arylthio (forexample phenylthio), or an aryl or aliphatic ester group such asbenzoate or acetate.

and thereafter or simultaneously therewith effecting one or more of thefollowing further steps may be additionally performed in any desired ornecessary order:

(i) removing any remaining protecting group(s);

(ii) converting a compound of formula (I) or a protected form thereofinto a further compound of formula (I) or a protected form thereof;

(iii) converting the compound of formula (I) or a protected form thereofinto a pharmaceutically acceptable derivative of the compound of formula(I) or a protected form thereof;

(iv) converting a pharmaceutically acceptable derivative of the compoundof formula (I) or a protected form thereof into the compound of formula(I) or a protected form thereof;

(v) converting a pharmaceutically acceptable derivative of the compoundof formula (I) or a protected form thereof into another pharmaceuticallyacceptable derivative of the compound of formula (I) or a protected formthereof;

(vi) where necessary, separating the alpha and beta anomers of thecompound of formula (I) or of a protected derivative thereof or of apharmaceutically acceptable derivative of a compound of formula (I)

Process A may conveniently be used for the preparation of a compound offormula (I) wherein R is halogen. Such compounds may conveniently beprepared by reacting a compound of formula (II) wherein L is hydrogenand R³, R⁴ and R⁵ are protected hydroxy groups, preferably OC(O)CH₃,with a halogenating agent. Halogenation may be effected in aconventional manner, for example, bromination using a brominating agentsuch as N-bromosuccinimide (NBS) in an aprotic solvent such as THF orpreferably 1,4 dioxane heated to 60-150° C., preferably 100° C.

Compounds of formula (I) wherein R is --NR¹ R² (wherein R¹ and R² are ashereinbefore defined) may advantageously be prepared from compounds offormula (II) wherein L is a halo atom, such as a bromo or chloro atom.By reaction with an amine H--NR¹ R² (wherein R¹ and R² are ashereinbefore defined). The reaction is advantageously effected at anelevated temperature, for example, 70-80° C., in an organic solvent suchas ethanol or dimethylsulfoxide.

The protecting groups may be removed by conventional chemical techniqueswell known to a skilled person.

Compounds of formula (II) wherein R³, R⁴ and R⁵ are each a hydroxy groupcan, for example, be prepared from a corresponding compound of formula(II) wherein R³, R⁴ and R⁵ are each a protected hydroxy group.Conventional protecting groups may be used for R³, R⁴ and R⁵.Advantageously ester groups such as those described above in relation tothe esters of the compounds of formula (I) may be used. These protectinggroups may be removed either by conventional chemical techniques such assodium carbonate in methanol or enzymatically, for example, using pigliver enzyme. Alternatively, R³, R⁴ and R⁵ may include silyl protectinggroups such as tert-butyldiphenyl-, tert-butyldimethyl-,triisopropropyl-silyl groups which may be removed using an appropriatefluoride source, for example HF/Pyridine, n-Bu₄ NF or Et₄ NF or a cyclicacetal or ketal such as benzylidene or isopropylidene groups which canbe removed under acidic conditions, for example, using tosic acid andmethanol.

Alternatively, the compound of formula (II) where R³, R⁴ and R⁵ areprotected hydroxy groups may be reacted with an agent or underconditions whereby the leaving group L is converted to the desired Rgroup simultaneously with removal of the protecting groups. Examples ofsuch agents include cyclopropylamine and other primary and secondaryamines providing that these agents are sufficiently nucleophilic and arenot sterically hindered.

Compounds of formula (I) wherein R is as hereinbefore defined andcompounds of formula (II) wherein L is as hereinbefore defined may beprepared by reacting a compound of formula (V) ##STR7## (wherein X isequivalent to R or L as hereinbefore defined) with a compound of formula(IV) ##STR8## (wherein R³, R⁴ and R⁵ are each a hydroxy or a protectedhydroxy group and L¹ is as hereinbefore defined.

The reaction of the compounds of formula (IV) and (V) may be effectedusing a Lewis acid such as trimethylsilyl triflate, stannictetrachloride, or boron trifluoride, the former being preferred. Thereaction is generally effected in an aprotic solvent and at an elevatedtemperature, for example, in acetonitrile at 15-30° C. or1,2-dichloroethane at 70-90° C.

The compound of formula (V) is advantageously trimethylsilylated at theN₁ -position in the above procedures to improve solubility; for exampleby treatment with trimethylsilyl chloride, hexamethyl disilazane or,most preferably, N,O-bis-trimethylsilyl acetamide (BSA). This silylationcan be effected in a solvent preferably 1,2-dichloroethane oracetonitrile preferably at 70-80°. After completion of the silylationreaction, a Lewis acid may be added followed by addition of the compoundof formula (IV).

Compounds of formula (IV) may be prepared by methods well known to askilled person, for example, in a manner analogous to that known forD-ribose derivatives or by methods readily available from the chemicalliterature, for example, by methods described in Acton et al. J. Am.Chem. Soc, 1964, 86, 5352. A preferred compound of formula (IV) is thecompound wherein R³, R⁴, R⁵ and L¹ are each OC(O)CH₃. This compound maybe prepared in an analogous manner to that developed for D-ribose (R. D.Guthrie and S. C. Smith., Chemistry and Industry, 1968, pp 547-548),followed advantageously by recrystallisation from ethanol.

The compounds of formula (V) wherein X is L or a --NR¹ R² group (whereinL, R¹ and R² are as hereinbefore defined), may be prepared in accordancewith the methods described in PCT specification WO92/07867 incorporatedherein by reference.

Alternatively, compounds of formula (V) wherein X is R and R is a group--NR¹ R² wherein R¹ and R² are as hereinbefore defined may be preparedby reacting a compound of formula (VI). ##STR9## with an agent or agentscapable of cyclising the diamine into a benzimidazole. Typicallycompounds of formula (I) may be reacted with an isothiocyanate offormula (VII)

    S═C═NR.sup.1 R.sup.2                               (VII)

wherein R¹ and R² are as hereinbefore defined.

The reaction may be carried out in the presence of a carbodiimide suchas dicyclohexyl carbodiimide or1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluene-sulphonate conveniently in the presence of an aproticaromatic solvent such as toluene and most preferably pyridine and at anelevated temperature, preferably 75-150° C.

Compounds of formula (V) wherein X is hydrogen may be obtainedcommercially or alternatively may be prepared by reacting a compound offormula (VI) with formamidine under aqueous acidic conditions, at roomtemperature to 80° C.

Compounds of formula (VI) and (VII) may be prepared by methods wellknown to a skilled person or readily available in the chemicalliterature or obtained commercially.

Esters according to the invention may be prepared by methods well knownin the art, for example, a compound of formula (I) may be converted intoa pharmaceutically acceptable ester by reaction with an appropriateesterifying agent, for example, an appropriate acid halide or anhydride.

A compound of formula (I) may be converted into a correspondingpharmaceutically acceptable ether of formula (I) by reaction with anappropriate alkylating agent in a conventional manner.

The compounds of formula (I) including esters thereof, may be convertedinto pharmaceutically acceptable salts thereof in conventional manner,for example by treatment with the appropriate acid. An ester or salt ofan ester of formula (I) may be converted into the parent compound, forexample, by hydrolysis.

The beta and alpha anomers may be separated and isolated in pure form bysilica gel chromatography using a single solvent or a combination ofsolvents such as 1:20 methanol:dichloromethane.

The present invention further includes the compounds of formula (II) ashereinbefore defined as novel intermediates. Preferred compounds offormula (II) include those wherein L is hydrogen or a halo atom,preferably chloro or bromo, and R³, R⁴ and R⁵ are hydroxy or protectedhydroxy groups, preferably OC(O)CH₃.

Particularly preferred compounds of formula (II) are2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazoleand 2-bromo-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazole.

The present invention also includes the intermediates of formula (V)wherein X is R and R is a group --NR¹ R² wherein R¹ and R² are ashereinbefore defined with the proviso that R¹ and R² are not bothhydrogen or methyl.

Preferred compounds of formula (V) include2-(cyclopropylamino)-5,6-dichloro-1H-benzimidazole;5,6-dichloro-2-(isopropylamino)-1H-benzimidazole and5,6-dichloro-2-(2-fluoro-1-methylethylamino)-1H-benzimidazole.

The following Examples are intended for illustration only and are notintended to limit the scope of the invention in any way. The term`active ingredient` as used in the Pharmaceutical examples means acompound of formula (I) or a pharmaceutically acceptable derivativethereof. The term also covers a compound of formula (I) or apharmaceutically acceptable derivative thereof in combination with oneor more therapeutic agents.

EXAMPLE 12-Bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

2-Bromo-5,6-dichlorobenzimidazole (1.0 g, 3.8 mmol),N,O-bis(trimethylsiyl) acetamide (Aldrich, 0.94 mL, 3.8 mmol), andacetonitrile (Aldrich Sure Seal, 25 mL) were combined and refluxed undernitrogen for 1 h. The solution was cooled to rt and trimethylsilyltriflate (Aldrich, 1.5 mL, 7.6 mmol) was added. After 15 min, solid1,2,3,5-tetra-O-acetyl-L-ribofuranose (1.2 g, 3.8 mmol), prepared by themethod of Guthrie and Smith (Chemistry and Industry, 1968, pp 547-548)except that L-ribose was used as the starting material, was added. Thesolution was stirred under nitrogen at rt for 18 h, then poured into 10%aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane(2×150 mL). The organic layers were dried with magnesium sulfate(anhyd), filtered, and evaporated. The crude residue was purified on asilica gel column (5×20 cm, 230-400 mesh) with 1:30 acetone : CH₂ Cl₂ togive2-bromo-5,6-dichloro-1-(3,4,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(1.2 g, 2.2 mmol, 60%); m.p. 142° C.; [a]²⁰ _(D) =(+) 87.4 (c=0.5 DMF);UV l_(max) (e) pH=7.0: 298 nm (7,600), 289 (7,400), 254 (8,800); 0.1 NNaOH: 298 nm (7,600), 289 (7,400), 256 (7,300); MS (EI): m/z (rel.intensity) 524 (0.15, M⁺); ¹ H NMR (DMSO-d₆) d 8.08 (s, 1H, Ar--H), 8.01(s, 1H, Ar--H), 6.22 (d, 1H, H-1', J=7.1 Hz), 5.56 (dd, 1H, H-2', J=7.1Hz, J=7.2 Hz), 5.45 (dd, 1H, H-3', J=7.2 Hz, J=4.5 Hz), 4.55-4.47 (m,2H, H-4' and 5'), 4.37 (d, 1H, H-5", J=9.7 Hz), 2.15 (s, 3H, OAc), 2.14(s, 3H, OAc), 2.01 (s, 3H, OAc).

Anal. Calcd. for C₁₈ H₁₇ N₂ O₇ Cl₂ Br: C, 41.25; H, 3.27; N, 5.34.Found: C, 41.16; H, 3.39; N, 5.20.

In addition, a small amount of the alpha anomer(2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-alpha-L-ribofuranosyl)-1H-benzimidazole)was obtained (0.11 g, 0.22 mmol, 6%); m.p. <65° C.; [a]²⁰ _(D) =(-)206.8 (c=0.5 DMF); MS (AP+): m/z (rel. intensity): 524 (0.8, M⁺); ¹ HNMR (DMSO-d₆) d 7.95 (s, 1H, Ar--H), 7.91 (s, 1H, Ar--H), 6.66 (d, 1H,H-1', J=4.2 Hz), 5.68 (t, 1H, H-2', J=4.6 Hz), 5.52 (t, 1H, H-3', J=5.9Hz), 4.87-4.81 (m, 1H, H-4'), 4.37-4.24 (m, 2H, H-5'), 2.08 (s, 3H,OAc), 2.03 (s, 3H, OAc), 1.51 (s, 3H, OAc).

Anal. Calcd. for C₁₈ H₁₇ N₂ O₇ Cl₂ Br: C, 41.25; H, 3.27; N, 5.34.Found: C, 41.39; H, 3.35; N, 5.29.

EXAMPLE 2 2-Bromo-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Sodium carbonate (0.28 g, 2.65 mmol) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(1.39 g, 2.65 mmol) were combined with water (4 mL), methanol (20 mL)and ethanol (20 mL) and stirred at rt for 1.5 h. Acetic acid (0.3 mL,5.3 mmol) was added and the suspension was concentrated to a solid.Purification of the residue on a silica gel column (2.5×20 cm, 230-400mesh) with 1:9 ethanol: CH₂ Cl₂ gave2-bromo-5,6-dichloro-1-beta-L-ribofuranosyl-1H-benzimidazole as a whiteamorphous solid (0.79 g, 2.0 mmol, 75%); m.p. 169° C.; [a]²⁰ _(D) =(+)105 (c=0.5 DMF); UV l_(max) (e): pH 7.0: 298 nm (6,700), 289 (6,500),255 (6,900); 0.1 N NaOH: 298 nm (6,700), 295 (5,400), 256 (6,700); MS(CI): m/z 399 (M+1); ¹ H NMR (DMSO-d₆) d 8.57 (s, 1H, Ar--H), 7.96 (s,1H, Ar--H), 5.89 (d, J=7.9 Hz, H-1'), 5.48 (d, 1H, OH, J=6.3 Hz), 5.42(t, 1H, OH, J=4.5 Hz), 5.29 (d, 1H, OH, J=4.2 Hz), 4.43 (apparent dd,1H, H-2', J=13.3 Hz, J=6.1 Hz), 4.14 (apparent t, 1H, H-3', J=4.3 Hz),4.01 (apparent d, 1H, H-4', J=1.7 Hz), 3.77-3.63 (m, 2H, H-5').

Anal. Calcd. for C₁₂ H₁₁ N₂ O₄ Cl₂ Br. 0.20 C₂ H₆ O: C, 36.57; H, 3.02;N, 6.88. Found: C, 36.68; H, 2.85; N, 7.05.

EXAMPLE 32-(Cyclopropylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Cyclopropylamine (5 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.10 g, 0.25 mmol) were combined with absolute ethanol (5 mL) andstirred at 75° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×14 cm, 230-400 mesh) with 1:20methanol:dichloromethane to give 0.073 g of product. This material wasfurther purified on a second silica gel column (2.5 cm×10 cm, 230-400mesh) with 1:5:5 methanol: ethyl acetate:hexanes to give a white solid(0.051 g, 0.14 mmol, 55%); m.p. 228-230° C. (dec); [a]²⁰ _(D) =(-) 17.4(c=0.5 Ethanol, Abs); UV l_(max) (e): pH 7.0: 303 nm (10,400), 274(1,700), 259 (9,100); 0.1 N NaOH: 304 nm (10,700), 295 (1,900), 259(8,800); MS (CI): m/z (rel. intensity) 374 (13.2, M+1); ¹ H NMR(DMSO-d₆) d 7.6 (s, 1H, Ar--H), 7.42 (s, 1H, Ar--H), 5.71 (d, 1H, J=7.6Hz, H-1'), 5.65 (t, 1H, OH, J=4.3 Hz), 5.25-5.21 (m, 2H, OH), 4.22(apparent dd, 1H, H-2', J=13.4 Hz, J=7.6 Hz), 4.02 (apparent t, 1H,H-3', J=7.1 Hz), 3.95 (s, 1H, H-4'), 3.67-3.62 (m, 2H, H-5'), 2.78-2.74(m, 1H, cyclopropyl-CH), 0.67 (d, 2H, J=7.1 Hz, cyclopropyl-CH₂),0.53-0.47 (m, 2H, cyclopropyl-CH₂).

Anal. Calcd. for C₁₅ H₁₆ N₃ O₄ Cl₂. 0.50 C₄ H₈ O₂. 0.15 C₆ H₁₄ : C,49.98; H, 5.18; N, 9.77. Found: C, 49.86; H, 5.18; N, 9.80.

EXAMPLE 42-(Allylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Allylamine (5 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.60 g, 1.14 mmol) were combined with absolute ethanol (10 mL) andstirred at 75° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×20 cm, 230-400 mesh) with 1:9methanol:dichloromethane to give a off white solid (0.325 g, 0.87 mmol,76%); m.p. 220° C. (dec); [a]²⁰ _(D) =(-) 16.0 (c=0.5 DMF); UV l_(max)(e): pH 7.0: 303 nm (11,200), 275 (2,000), 259 (9,900); 0.1 N NaOH: 304nm (11,300), 275 (2,000),259 (9,200); MS (CI): m/z (rel. intensity) 374(100, M+1); ¹ H NMR (DMSO-d₆) d 7.66 (s, 1H, Ar--H), 7.35 (s, 1H,Ar--H), 5.98-5.85 (m, 1H, CH═CH₂), 5.76 (d, 1H, J=7.6 Hz, H-1'), 5.62(t, 1H, OH, J=4.3 Hz), 5.28 (d, 1H, OH, J=7.6 Hz), 5.23 (d, 1H, OH,J=4.2 Hz), 5.16 (d, 1H, CH═CH₂, J=18.6 Hz), 5.05 (d, 1H, CH═CH₂, J=10.2Hz), 4.30 (apparent dd, 1H, H-2', J=13.1 Hz, J=7.6 Hz), 4.06 (apparentt, 1H, H-3', J=5.6 Hz), 3.97 (br. s, 1H, H-4', CH₂ CH═CH₂), 3.71-3.60(m, 2H, H-5').

Anal. Calcd. for C₁₅ H₁₇ N₃ O₄ Cl₂. 0.30 H₂ O: C, 47.46; H, 4.67; N,11.07. Found: C, 47.50; H, 4.68; N, 11.02.

EXAMPLE 55,6-Dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Isopropylamine (10 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(1.0 g, 1.9 mmol) were combined with absolute ethanol (20 mL) andstirred at 75° C. for 48 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20methanol:dichloromethane to give product contaminated with a smallamount of higher R_(f) material. This was repurified on a chromatotron,fitted with a 2 mm silica gel rotor, with 1:25 methanol:dichloromethaneto give a white solid (0.43 g, 1.15 mmol, 60%); [a]²⁰ _(D) =(-) 22.4(c=0.5 DMF); UV l_(max) (e): pH 7.0: 304 nm (9,500), 275 (1,800), 260(8,300); 0.1 N NaOH: 304 nm (9,900), 275 (1,900), 260 (8,100); MS (CI):m/z (rel. intensity) 376 (100, M+1); ¹ H NMR (DMSO-d₆) d 7.59 (s, 1H,Ar--H), 7.35 (s, 1H, Ar--H), 6.90 (d, 1H, NH, J=7.8 Hz), 5.73 (d, 1H,H-1', J=6.5 Hz), 5.62 (t, 1H, OH, J=4.2 Hz), 5.27-5.23 (m, 2H, OH), 4.27(apparent dd, 1H, J=13.4 Hz, J=7.6 Hz), 4.11-3.99 (m, 2H), 3.97 (br. s,1H), 3.72-3.61 (m, 2H, H-5'), 1.18 (d, 6H, CH(CH₃)₂, J=6.6 Hz).

Anal. Calcd. for C₁₅ H₁₉ N₃ O₄ Cl₂. 1.00 H₂ O: C, 45.70; H, 5.37; N,10.66. Found: C, 45.75; H, 4.98; N, 10.50.

EXAMPLE 62-(Cyclopentylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Cyclopentylamino (5 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 70° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:9ethanol:dichloromethane to give a white solid (0.27 g, 0.68 mmol, 59%);m.p. 140° C.; [a]²⁰ _(D) =(-) 24.0 (c=0.5 DMF) UV l_(max) (e): pH7.0:305 nm (12,700), 276 (2,400), 260(10,600), 245(7400); 0.1 N NaOH: 305 nm(12,600), 276 (2,200),260 (9,900), 247 (7,300); MS (CI): m/z (rel.intensity) 402 (100 , M+1); ¹ H NMR (DMSO-d₆) d 7.60 (s, 1H, Ar--H ),7.36 (s, 1H, Ar--H), 6.91 (d, 1H, NH, J=6.8 Hz), 5.74 (d, 1H, H-1',J=7.6 Hz), 5.61 (t, 1H, OH, J=4.2 Hz), 5.26 (d, 1H, OH, J=8.1 Hz), 5.23(d, 1H, OH, J=5.5 Hz), 430-4.14 (m, 2H, NHCH, H-2'), 4.05 (apparent t,1H, H-3', J=4.9 Hz), 3.96 (br. s, 1H, H-4'), 3.72-3.59 (m, 2H, H-5'),1.91 (br. s, 2H, CH₂), 1.66 (br. s, 2H, CH₂), 1.52 (br. s, 4H, CH₂).

Anal. Calcd. for C₁₇ H₂₁ N₃ O₄ Cl₂. 0.20 H₂ O: C, 50.31; H, 5.31; N,10.38. Found: C, 50.13; H, 5.31; N, 10.05.

EXAMPLE 72-(Benzylamino)-5,6-dichloro-1-r(beta-L-ribofuranosyl)-1H-benzimidazole

Benzylamine (10 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(1.0 g, 1.9 mmol) were combined with absolute ethanol (20 mL) andstirred at 70° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:9ethanol:dichloromethane. The crude product contained benzylamine. Thismaterial was further purified on a second silica gel column (2.5 cm×16cm, 230-400 mesh) with 3:7 acetone:hexanes to give product with a smallamount of impurity. A third silica gel column, identical to the secondwas used for final purification to give an off white solid (0.26 g, 0.62mmol, 32%); m.p. 123° C.; [a]²⁰ _(D) =(-) 4.6 (c=0.5 DMF); UV l_(max)(e): pH 7.0: 304 nm (10,600), 276 (1,800), 260 (9,600); 0.1 N NaOH: 305nm (10,500), 276 (1,500), 260 (8,500); MS (CI): m/z (rel. intensity) 424(100, M+1); ¹ H NMR (DMSO-d₆) d 7.78 (t, 1H, J=5.9 Hz, NH), 7.68 (s, 1H,Ar--H), 7.34 (s, 1H, Ar--H), 7.34-7.18 (m, 5H, Ar--H), 5.80 (d, 1H,H-1', J=7.6 Hz), 5.67 (t, 1H, OH, J=4.1 Hz), 5.32 (d, 1H, OH, J=7.6 Hz),5.25 (d, 1H, OH, J=4.6 Hz), 4.55 (d, 2H, PhCH₂, J=5.7 Hz), 4.34(apparent dd, 1H, H-2', J=13.1 Hz, J=7.4 Hz), 4.08 (apparent t, 1H,H-3', J=3.8 Hz), 4.00 (br. s, 1H, H-4'), 3.73-3.61 (m, 2H, H-5').

Anal. Calcd. for C₁₉ H₁₉ N₃ O₄ Cl₂. 0.10 H₂ O: C, 53.56; H, 4.54; N,9.86. Found: C, 53.23; H, 4.62; N, 9.71.

EXAMPLE 82-Azetidino-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Azetidine (1 g ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 75° C. for 72 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20methanol:dichloromethane to give an off white solid (0.35 g, 0.93 mmol,82%); m.p. 244-245° C.; [a]²⁰ _(D) =(+)69.6 (c=0.5 DMF); UV l_(max) (e):pH 7.0: 305 mn (9,900), 275 (1,500), 260 (9,800); 0.1 N NAOH: 305 nm(9,800), 276 (1,600), 260 (7,800); MS (CI): m/z (rel. intensity) 376(100, M+1); ¹ H NMR (DMSO-d₆) d 8.60 (s, 1H, Ar--H), 7.49 (s, 1H,Ar--H), 5.43 (d, 1H, H-1', J=7.6 Hz), 5.33 (d, 1H, OH, J=6.6 Hz), 5.26(t, 1H, OH, J=4.7 Hz), 5.13 (d, 1H, OH, J=4.7 Hz), 4.35 (apparent dd,1H, H-2', J=12.6 Hz, J=6.0 Hz), 4.17 (t, 4H, CH₂, J=7.6 Hz), 4.07(apparent t, 1H, H-3', J=6.1 Hz), 3.88 (d, 1H, H-4', J=2.4 Hz), 3.64(br. s, 2H, H-5'), 2.39-2.29 (m, 2H, CH₂).

Anal. Calcd. for C₁₅ H₁₇ N₃ O₄ Cl₂ : C, 48.14; H, 4.58; N, 11.23. Found:C, 48.00; H, 4.59; N, 11.15.

EXAMPLE 95,6-Dichloro-2-(propargylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Propargylamine (4 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 70° C. for 4 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20ethanol:dichloromethane to give 0.18 g of crude product. This materialwas further purified on a chromatotron, fitted with a 2 mm rotor, using1:9 methanol:dichloromethane to give a light yellow solid (0.135 g, 0.36mmol, 32%); m.p. 182-184° C.; [a]²⁰ _(D) =(-) 9.2 (c=0.5 DMF); UVl_(max) (e): pH 7.0: 300 nm (8,900), 272 (1,700), 258 (8,300); 0.1 NNaOH: 301 nm (8,700), 272 (1,800), 259 (7,500); MS (CI): m/z (rel.intensity) 372 (100, M+1); ¹ H NMR (DMSO-d₆) d 7.73 (s, 1H, Ar--H), 7.58(t, 1H, J=5.5 Hz, NH), 7.43 (s, 1H, Ar--H), 5.75 (d, 1H, H-1', J=5.0Hz), 5.66 (t, 1H, OH, J=4.3 Hz), 5.29 (d, 1H, OH, J=7.6 Hz), 5.24 (d,1H, OH, J=4.2 Hz), 4.28 (apparent dd, 1H, H-2', J=13.2 Hz, J=7.4 Hz),4.11-4.04 (m, 3H, H-3', CH₂), 3.97 (br. s, 1H, H-4'), 3.73-3.61 (m, 2H,H-5'), 3.10 (s, 1H, CH).

Anal. Calcd. for C₁₅ H₁₅ N₃ O₄ Cl₂. 0.75 H₂ O: C, 46.71; H, 4.31; N,10.89. Found: C, 46.52; H, 4.23; N, 10.72.

EXAMPLE 105,6-Dichloro-2-(n-propylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Propylamine (7 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 70° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:9ethanol:dichloromethane to give an off white solid (0.36 g, 0.96 mmol,84%); m.p. 231-233° C.; [a]²⁰ _(D) =(-) 23.6 (c=0.5 DMF); UV l_(max)(e): pH 7.0: 305 nm (9,900), 275 (1,500), 260 (9,800); 0.1 N NaOH: 305nm (9,800), 276 (1,600), 260 (7,800; MS (CI): m/z (rel. intensity) 376(100, M+1); ¹ H NMR (DMSO-d₆) d 7.60 (s, 1H, Ar--H), 7.35 (s, 1H,Ar--H), 7.15 (t, 1H, J=5.4 Hz, NH), 5.74 (d, 1H, H-1', J=7.6 Hz), 5.66(t, 1H, OH, J=4.0 Hz), 5.28 (d, 1H, OH, J=7.6 Hz), 5.24 (d, 1H, OH,J=4.2 Hz), 4.34-4.25 (m, 1H, H-2'), 4.06 (apparent t, 1H, H-3', J=4.7Hz), 4.00 (br. s, 1H, H-4'), 3.72-3.61 (m, 2H, H-5'), 3.31-3.24 (m, 2H,NH₂ CH₂), 1.57 (q, 2H, J=7.3 Hz, CH₂), 0.88 (t, 3H, J=7.5 Hz, CH₃).

Anal. Calcd. for C₁₅ H₁₉ N₃ O₄ Cl₂. 0.25 H₂ O: C, 47.32; H, 5.16; N,11.04. Found: C, 47.43; H, 5.20; N, 10.74.

EXAMPLE 115,6-Dichloro-2-(isobutylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Isobutylamine (10 ml ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (50 mL) andstirred at 75° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20methanol:dichloromethane (500 mL), then 1:9 methanol:dichloromethane togive a tan solid (0.39 g, 1.0 mmol. 90%); m.p. 136° C.; [a]²⁰ _(D) =(-)28.4 (c=0.5 DMF).

Anal. Calcd. for C₁₆ H₂₁ N₃ O₄ Cl₂ : C, 48.13; H, 5.55; N, 10.52. Found:C, 48.08; H, 5.57; N, 10.41.

EXAMPLE 122-((5,6-Dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazol-2-yl)amino)ethanol

Ethanolamine (25 ml ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.62 g, 1.2 mmol) were combined with absolute ethanol (50 mL) andstirred at 80° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:20methanol:dichloromethane (500 mL), then 1:9 methanol:dichloromethane.Crude product was obtained which was further purified on a silica gelfilter pad with 1:1 acetone: dichloromethane and then with 1:2ethanol:dichloromethane. Further purification on a chromatotron fittedwith a 2 mm rotor, using 1:6 ethanol: ethyl acetate provided pureproduct (0.064 g, 0.17 mmol, 14%); [a]²⁰ _(D) =(-) 14.2 (c=0.5 DMF).

Anal. Calcd. for C₁₄ H₁₇ N₃ O₅ Cl₂. 0.50 H₂ O: C, 43.43; H, 4.69; N,10.85. Found: C, 43.74; H, 5.02; N, 10.53.

EXAMPLE 135,6-Dichloro-2-((1-ethylpropyl)amino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

1-Ethylpropylamine (5 ml ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (20 mL) andstirred at 80° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:15methanol:dichloromethane to give product (0.31 g) with a small amount ofimpurity. This material was further purified on a chromatotron, fittedwith a 2 mm rotor, using 1:2 acetone:dichloromethane to give a whitesolid (0.24 g, 0.59 mmol, 52%); [a]²⁰ _(D) =(-) 39.4 (c=0.5 DMF).

Anal. Calcd. for C₁₇ H₂₃ N₃ O₄ Cl₂ : C, 50.50; H, 5.73; N, 10.39. Found:C, 50.44; H, 5.88; N, 10.14.

EXAMPLE 142-(Cyclohexylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Cyclohexylamine (5 ml) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (20 mL) andstirred at 80° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:15methanol:dichloromethane to give product (0.38 g) with a small amount ofimpurity. This material was further purified on a chromatotron, fittedwith a 2 mm rotor, using 1:2 acetone:dichloromethane to give, inaddition to 0.25 g of slightly impure material, pure product as a whitesolid (0.059 g, 0.14 mmol, 12%); [a]²⁰ _(D) =(-) 24.0 (c=0.5 DMF).

Anal. Calcd. for C₁₈ H₂₃ N₃ O₄ Cl₂. 0.30 H₂ O: C, 51.27; H, 5.64; N,9.96. Found: C, 51.18; H, 5.68; N, 9.88.

EXAMPLE 152-Anilino-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Aniline (5 ml ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (35 mL) andstirred at 80° C. for 14 days. The reaction mixture was concentrated andthe aniline was distilled off under high vacuum at 80° C. The brownresidue was dissolved in methanol (50 mL) and K₂ CO₃ was added. Thissolution was stirred for 18 h. The solution was filtered, concentratedand purified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with1:15 methanol:dichloromethane to give a white solid (0.024 g, 0.06 mmol,5%). MS (AP+): m/z (rel. intensity) 410 (19.39, M+1); ¹ H NMR (DMSO-d₆)d 9.09 (s, 1H, NH), 7.83 (s, 1H, Ar--H), 7.78 (d, 1H, Ar--H, J=7.9 Hz),7.58 (s, 2H, Ar--H), 7.31 (t, 2H, Ar--H, J=7.9 Hz), 6.99 (t, 1H, Ar--H,J=7.5 Hz), 5.95 (d, 1H, H-1', J=7.8 Hz), 5.86 (t, 1H, OH, J=4.4 Hz),5.38 (d, 1H, OH, J=7.6 Hz), 5.30 (d, 1H, OH, J=4.2 Hz), 4.33 (apparentdd, 1H, H-4', J=13.4 Hz, J=7.8 Hz), 4.11 (apparent t, 1H, H-2', J=4.8Hz), 4.05 (s, 1H, H-4'), 3.79-3.71 (m, 2H, H-5').

EXAMPLE 165,6-Dichloro-2-(n-pentylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

n-Pentylamine (5 ml ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 80° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×16 cm, 230-400 mesh) with 1:15methanol:dichloromethane to give 0.55 g of product with some impurities.This material was repurified on a second silica gel column (2.5 cm×16cm, 230-400 mesh) with 1:20 methanol:dichloromethane to give anoff-white solid (0.40 g, 0.99 mmol, 87%) m.p. 102-103° C.; [a]²⁰ _(D)=(-) 22.0 (c=0.5 DMF).

Anal. Calcd. for C₁₇ H₂₃ N₃ O₄ Cl₂ : C, 50.50; H, 5.73; N. 10.40. Found:C, 50.25; H, 5.85; N, 10.26.

EXAMPLE 172-((5,6-Dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazol-2-yl)amino)acetonitrile

Amino acetonitrile hydrochloride (1.2 g, 13 mmol), triethylamine (5 mL),and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (40 mL) andstirred at 80° C. for 3 days. The reaction mixture was concentrated andthe residue was diluted with ethyl acetate (150 mL) and extracted with10% sodium bicarbonate (25 mL) then with water (2×25 mL). The ethylacetate layer was dried (Na₂ SO₄) decanted and concentrated to a brownoil (0.67 g) and purified on a silica gel column (2.5 cm×18 cm, 230-400mesh) with 1:15 methanol:dichloromethane. The two main products off thecolumn were2-bromo-5,6-dichloro-1-(5-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.32 g) and2-bromo-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole (0.14 g).A lower R_(f) material (0.19 g) was also isolated and further purifiedon a chromatotron fitted with a 2 mm rotor using 1:20methanol:dichloromethane to give an off white solid (0.024 g, 0.06 mmol,5%); MS (AP-): m/z (rel. intensity) 371 (80, M-2); ¹ H NMR (DMSO-d₆) d7.87 (t, 1H, NH, J=5.9 Hz), 7.83 (s, 1H, Ar--H), 7.52 (s, 1H, Ar--H),5.74 (d, 1H, H-1', J=7.6 Hz), 5.68 (t, 1H, OH, J=4.1 Hz), 5.32 (d, 1H,OH, J=7.1 Hz), 5.23 (d, 1H, OH, J=4.2 Hz), 4.37 (d, 2H, CH₂ CN, J=5.3Hz), 4.28 (apparent dd, 1H, H-4', J=13.0 Hz, J=7.2 Hz), 4.07 (apparentt, 1H, H-3', J=3.5 Hz), 3.98 (s, 1H, H-3'), 3.73-3.63 (m, 2H, H-5').

Anal. Calcd. for C₁₄ H₁₄ N₄ O₄ Cl₂. 0.30 CH₄ O. 0.15 CH₂ Cl₂ : C, 43.88;H, 3.95; N, 14.16. Found: C, 43.81; H, 3.90; N, 14.21.

EXAMPLE 182-(n-Butylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

n-Butylamine (5 mL), and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 80° C. for 18 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×18 cm, 230-400 mesh) with 1:9methanol:dichloromethane. Crude product was obtained (0.73 g) which wasfurther purified on a chromatotron, fitted with a 2 mm rotor, using 1:2acetone:dichloromethane to give an off white solid (0.20 g, 0.51 mmol,45%) m.p. 220-222° C.; [a]²⁰ _(D) =(-) 17.2 (c=0.5 DMF).

Anal. Calcd. for C₁₆ H₂₁ N₃ O₄ Cl₂. 1/10 H₂ O. 1/2 C₃ H₆ O: C, 49.91; H,5.79; N, 9.98. Found: C, 49.75; H, 5.90; N, 10.16.

EXAMPLE 192-(sec-Butylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

sec-Butylamine (3 mL), and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 80° C. for 18 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×18 cm, 230-400 mesh) with 1:20methanol:dichloromethane. Crude product was obtained (0.37 g) which wasfurther purified on a chromatotron, fitted with a 2 mm rotor, using 1:20methanol:dichloromethane to give an off white solid which was a mixtureof diastereomers (0.21 g, 0.55 mmol, 48%) m.p. 121-122° C.; [a]²⁰ _(D)=(-) 23.8 (c=0.5 DMF).

Anal. Calcd. for C₁₆ H₂₁ N₃ O₄ Cl₂. 7/10 H₂ O: C, 47.70; H, 5.60; N,10.43. Found: C, 47.76 H, 5.51; N, 10.16.

EXAMPLE 202-(Cyclobutylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Cyclobutylamine (3 mL), and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (10 mL) andstirred at 80° C. for 24 h. The reaction mixture was concentrated andpurified on a silica gel column (2.5 cm×18 cm, 230-400 mesh) with 2:1ethyl acetate:hexanes. Crude product was obtained (0.42 g) which wasfurther purified by multiple cyclings on a chromatotron, fitted with a 2mm rotor, using 1:20 methanol:dichloromethane to give a white solid(0.26 g, 0.67 mmol, 59%) m.p. 220-221° C.; [a]²⁰ _(D) =(-) 22.4 (c=0.5DMF).

Anal. Calcd. for C₁₆ H₁₉ N₃ O₄ Cl₂ : C, 49.50; H, 4.93; N, 10.82. Found:C, 49.22 H, 4.90; N, 10.61.

EXAMPLE 212-(Cycloheptylamino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Cycloheptylamine (2 mL), and2-bromo-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole (0.4 g,1.0 mmol) were combined with absolute ethanol (10 mL) and stirred at 80°C. for 24 h. The reaction mixture was concentrated and purified on asilica gel column (2.5 cm×18 cm, 230-400 mesh) with 1:20:20methanol:ethyl acetate:hexanes to give an off white solid (0.13 g, 0.3mmol, 30%) m.p. 137-138° C.; [a]²⁰ _(D) =(-) 21.6 (c=0.5 DMF).

Anal. Calcd. for C₁₆ H₁₉ N₃ O₄ Cl₂. 11/10 H₂ O: C, 50.70; H, 6.09; N,9.33. Found: C, 50.91 H, 5.91; N, 9.13.

EXAMPLE 225,6-Dichloro-2-((2-(1-pyrrolidinyl)ethyl)amino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

1-(2-Aminoethyl)pyrrolidine (1.9 mL, 13.5 mmol), triethylamine (2 mL),and 2-bromo-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole (0.6g, 1.1 mmol) were combined with absolute ethanol (10 mL) and stirred at80° C. for 18 h. The reaction mixture was concentrated and purified on asilica gel column (2.5 cm×18 cm, 230-400 mesh) with 1:20methanol:dichloromethane. The main product off the column was dissolvedin deionized water neutralized and extracted into dichloromethane togive an off white solid (0.26 g, 0.6 mmol, 53%) m.p. 123-124° C.; [a]²⁰_(D) =(-) 20.4 (c=0.5 DMF).

Anal. Calcd. for C₁₈ H₂₄ N₄ O₄ Cl₂. 3/2 H₂ O. 1/2 C₄ H₈ O₂ : C, 47.82,H, 6.22; N, 11.15. Found: C, 47.79 H, 6.06; N, 10.97.

EXAMPLE 232-((Cyclopropylmethyl)amino)-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

(Aminomethyl)cyclopropene hydrochloride (1.6 g, 15 mmol), tributylamine(2 mL), and2-bromo-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole (0.55 g,1.05 mmol) were combined with absolute ethanol (10 mL) and stirred at80° C. for 6 h. The reaction mixture was concentrated and purified on asilica gel column (2.5 cm×18 cm, 230-400 mesh) with 1:20methanol:dichloromethane. The main product off the column was repurifiedon a silica gel column (2.5 cm×18 cm, 230-400 mesh) with 1:10:10methanol:ethyl acetate:hexanes to give an off white solid (0.30 g, 0.77mmol, 74%) m.p. 229-230° C.; [a]²⁰ _(D) =(-) 24.8 (c=0.5 DMF).

Anal. Calcd. for C₁₆ H₁₉ N₃ O₄ Cl₂ : C, 49.50; H, 4.93; N, 10.83. Found:C, 49.30 H, 5.02; N, 10.66.

EXAMPLE 242-(tert-Butylamino)-5,6-dichloro-1-1(beta-L-ribofuranosyl)-1H-benzimidazole

A solution of2-(tert-butylamino)-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(2.0 g, 3.9 mmol) in methanol (40 mL) and ethanol (40 mL) was combinedwith a solution of sodium carbonate (0.61 g, 5.8 mmol) in water (10 mL).The solution was stirred at rt for 5 h, then the methanol and ethanolwere removed on the rotoevaporator. The solution was then extractedbetween ethyl acetate (150 mL) and saturated NaCl (20 mL). The organicswere concentrated and purified on a silica gel column (2.5 cm×14 cm,230-400 mesh) with 1:20 methanol:dichloromethane to give a white solid(1.25 g, 3.2 mmol, 83%) m.p. 118-120° C.; [a]²⁰ _(D) =(-) 30.2 (c=0.5DMF).

Anal. Calcd. for C₁₆ H₂₁ N₃ O₄ Cl₂ : 2/5 H₂ O. 2/5 CH₄ O C, 48.01; H,5.75; N, 10.24. Found: C, 48.20; H, 5.73; N, 10.05.

EXAMPLE 252-(tert-Butylamino)-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

Anhydrous 1,2-dichloroethane (15 mL),2-(tert-butylamino)-5,6-dichlorobenzimidazole (1.5 g, 5.84 mmol), andN,O-bistrimethylsilylacetamide (2.2 mL, 8.8 mmol) were combined andstirred at 80° C. for 30 min. Trimethylsilyl triflate (1.1 mL, 5.84mmol) was added and the solution was stirred at 80° C. for 45 min. Solid1,2,3,4-tetra-O-acetyl-L-ribofuranoside (L-TAR) (2.0 g, 6.42 mmol) wasadded and stirring was continued at 80° C. for 3 h. More L-TAR was added(0.5 g, 1.6 mmol) at this time. After 1 hr the reaction was quenchedwith cold saturated sodium bicarbonate (40 mL), then extracted withdichloromethane (2×150 mL). The combined organics were dried (sodiumsulfate), decanted, and concentrated to give 4.0 g of a gold solid. Thismaterial was purified on a silica gel column (5 cm×16 cm, 230-400 mesh)with 1:30 methanol:dichloromethane to give an off white solid (2.21 g,4.3 mmol, 73%); [a]²⁰ _(D) =(-) 28.4 (c=0.5 DMF).

Anal. Calcd. for C₂₂ H₂₇ N₃ O₇ Cl₂. 1 CH₄ O C, 50.37; H, 5.70; N, 7.66.Found: C, 50.74; H, 5.41; N, 7.28.

EXAMPLE 26 2-(tert-Butylamino)-5,6-dichloro-1H-benzimidazole

4,5-Dichlorophenylene diamine (8.0 g, 45.2 mmol) (Aldrich, Milwaukee,Wis.) was combined with tert-butyl isothiocyanate (6.3 mL, 49.7 mmol)(Aldrich, Milwaukee, Wis.) in anhydrous pyridine (100 mL). The solutionwas heated at 80° C. for 1 h under nitrogen.1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-ρ-toluene-sulphonate (24.9 g, 58.8 mmol) (Fluka Chemika) was addedalong with anhydrous pyridine (90 mL). This solution was heated at 90°C. for 2.5 h. The pyridine was removed by rotoevaporation, and theresidue was dissolved in ethyl acetate (300 μM) and extracted with water(4×100 mL). The ethyl acetate layer was treated with decolorizing carbonand washed through a silica gel filter pad (4×8 cm, 230-400 mesh) usingethyl acetate. The crude product was purifed on a silica gel column(5×16 cm, 230-400 mesh) using (1:4) ethyl acetate : hexane. Crudefractions were repurified on a second identical column using (1:3) ethylacetate : hexane. Pure fractions from the two columns were combined togive a tan solid (3.13 g, 12.1 mmol, 27%); m.p. 219-221° C.; MS (API+):m/z (rel. intensity) 258 (100, M+1); ¹ H NMR (DMSO-d₆) d 10.31 (s, 1H,NH), 7.31 (s, 2H, Ar--H), 6.61 (s, 1H, NH), 1.38 (s, 9H, t-butyl).

Anal. Calcd. for C₁₁ H₁₃ N₃ Cl₂ : C, 51.18; H, 5.08; N, 16.28. Found: C,51.11; H, 5.12; N, 16.18.

EXAMPLE 272-Amino-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

A solution of2-amino-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(1.0 g, 2.2 mmol) in methanol (17 mL) and ethanol (17 mL) was combinedwith a solution of sodium carbonate (0.25 g, 2.4 mmol) in water (4 mL).The solution was stirred at rt for 64 h, then the methanol and ethanolwere removed on the rotoevaporator. The solution was then extractedbetween ethyl acetate (2×100 mL) and saturated NaCl (20 mL). Theorganics were concentrated and purified on a silica gel column (2.5cm×14 cm, 230-400 mesh) with 1:10 methanol:dichloromethane to give awhite solid (4.1 g, 1.24 mmol, 57%) m.p. 110-112° C.; [a]²⁰ _(D) =(-)4.2 (c=0.5 DMF).

Anal. Calcd. for C₁₂ H₁₃ N₃ O₄ Cl₂. 3/5 H₂ O. 2/5 CH₄ O: C, 41.63; H,4.45; N, 11.74. Found: C, 41.47; H, 4.27; N, 11.58.

EXAMPLE 282-Amino-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

Anhydrous 1,2-dichloroethane (100 mL),2-amino-5,6-dichloro-benzimidazole (10 g, 49.5 mmol) (synthesized by themethod of Homer and Henry J. Med. Chem. 1968, 11, 946-949), andN,O-bistrimethylsilylacetamide (18.3 mL, 74.2 mmol) were combined andstirred at 80° C. for 30 min. all the solids dissolved. Trimethylsilyltriflate (9.3 mL, 48.3 mmol) was added and the solution was stirred at80° C. for 20 min. Solid 1,2,3,4-tetra-O-acetyl-L-ribofuranoside,(L-TAR), (17.3 g, 54.4 mmol), was added in four portions over a periodof 3 h while stirring was continued at 80° C. Fortyfive minutes afterthe last addition, the reaction was quenched with cold saturated sodiumbicarbonate (100 mL), then extracted with dichloromethane (200 mL). Thecombined organics were dried (sodium sulfate), decanted, andconcentrated to give 24.8 g of a thick red oil. This material waspurified on a silica gel column (5×20 cm, 230-400 mesh) with 1:40methanol:dichloromethane. NMR showed high R_(f) product from the columncontained a trimethylsilyl group. These fractions were reacted withtetrabutyl ammonium fluoride in THF for 24 h, and filtered through asilica gel filter pad with 1:10 methanol : dichloromethane.

All product containing fractions were combined and repurified on asilica gel column (5×14 cm, 230-400 mesh) with 1:1acetone:dichloromethane to give an off white solid (3.4 g, 7.4 mmol,15%); [a]²⁰ _(D) =(+) 48.0 (c=0.5 DMF).

Anal. Calcd. for C₁₈ H₁₉ N₃ O₇ Cl₂. 1/4 CH₂ Cl₂. 1/2 C₃ H₆ O: C, 46.46H, 4.44; N, 8.23. Found: C, 46.59; H, 4.35; N, 8.07.

EXAMPLE 295,6-Dichloro-1-(beta-L-ribofuranosyl)-2-((2,2,2-trifluoroethyl)amino-1H-benzimidazole

Triethylamine (2 mL), 2,2,2-trifluoroethylamine (2 mL), and2-bromo-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole (0.4 g,1.0 mmol) were combined with DMSO (10 mL) and stirred, in a sealed tube,at 80° C. for 17 days. The reaction mixture was extracted between water(30 mL) and dichloromethane (3×100 mL). The organics were concentratedand purified by multiple cyclings on a chromatotron fitted with a 2 mmrotor using 1:4 acetone:dichloromethane then 1:15methanol:dichloromethane to give an off white solid (0.02 g, 0.05 mmol,5%); MS (API+): m/z (rel. intensity) 416 (100, M⁺).

Anal. Calcd. for C₁₄ H₁₄ N₃ O₄ FCl₂. 1/2 H₂ O. 4/5 CH₄ O: C, 39.42; H,4.13; N, 9.25. Found: C, 39.34; H, 3.95; N, 9.08.

EXAMPLE 30 5,6-Dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

A solution of5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.43 g, 0.96 mmol) in methanol (10 mL) and ethanol (10 mL) was combinedwith a solution of sodium carbonate (0.15 g, 1.4 mmol) in water (2.5mL). The solution was stirred at rt for 24 h. then the methanol andethanol were removed on the rotoevaporator. The solution was thenextracted between ethyl acetate (4×100 mL) and saturated NaCl (20 mL).The organics were concentrated to give an analytically pure white solid(0.27 g, 0.85 mmol, 88%) m.p. 209-210° C.; [a]²⁰ _(D) =(+) 63 (c=0.5DMF).

Anal. Calcd. for C₁₂ H₁₂ N₂ O₄ Cl₂. 2/5 H₂ O. 1/10 C₄ H₈ O₂ : C, 44.44;H, 4.09; N, 8.36. Found: C, 44.49; H, 3.91; N, 8.14.

EXAMPLE 315,6-Dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

Anhydrous acetonitrile (20 mL), 5,6-dichloro-benzimidazole (EMS-DottikonAG) (0.59 g, 3.1 mmol), and N,O-bistrimethylsilylacetamide (0.77 mL, 3.1mmol) were combined and stirred at 80° C. for 30 min. All the solidsdissolved. Trimethylsilyl triflate (0.75 mL, 3.9 mmol) was added and thesolution was stirred at rt for 15 min during which time a large amountof solid formed. Solid 1,2,3,4-tetra-O-acetyl-L-ribofuranoside, (L-TAR),(1.0 g, 3.1 mmol), was added then the solution was warmed to 80° C. Allthe solids dissolved. After 1.5 h the reaction mixture was quenched withcold saturated sodium bicarbonate (10 mL), then extracted withdichloromethane (100 mL). The organics were dried (sodium sulfate),decanted, and concentrated to give 1.7g of a yellow oil. This materialwas purified on a silica gel column (2.5×18 cm, 230-400 mesh) with 1:40methanol:dichloromethane to give 1.37 g of a partially pure product. Asecond silica gel column (2.5×16 cm, 230-400 mesh) with 2:3 hexane:ethylacetate gave pure product as a white solid. (0.8 g, 1.78 mmol, 57%);[a]²⁰ _(D) =(+) 46.8 (c=0.5 DMF).

Anal. Calcd. for C₁₈ H₁₈ N₂ O₇ Cl₂ : C, 48.56 H,4.07; N, 6.29. Found: C,48.45; H, 4.11; N, 6.19.

EXAMPLE 322-Acetamido-5,6-dichloro-1-(beta-L-ribofuranosyl)-1H-benzimidazole

A solution of2-acetamido-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.35 g, 0.75 mmol) in methanol (8 mL) and ethanol (8 mL) was combinedwith a solution of sodium carbonate (0.12 g, 1.1 mmol) in water (2 mL).The solution was stirred at rt for 24 h, then the methanol and ethanolwere removed on the rotoevaporator. The solution was then extractedbetween ethyl acetate (2×150 mL) and saturated NaCl (20 mL). Theorganics were concentrated and purified by multiple cyclings on achromatotron, fitted with a 2 mm rotor, using 1:10methanol:dichloromethane to give a white solid (0.067 g, 0.18 mmol,23%); This material was identified by ¹ H NMR, MS and HPLC, it containedabout 7% of 2-amino-5,6-dichloro-beta-L-ribofuranosyl-1H-benzimidazoleby ¹ H NMR. HPLC showed two small (˜5%) impurities.

EXAMPLE 335,6-Dichloro-2-(methylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Methylamine hydrochloride (3.0 g, 45 mmol), triethylamine (3 mL), and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.6 g, 1.1 mmol) were combined with absolute ethanol (25 mL) andstirred at 80° C. for 24 h. The reaction mixture was separated betweensaturated sodium bicarbonate (50 mL) and ethyl acetate (150 mL). Theorganic layer was dried with sodium sulfate, concentrated and absorbedonto silica gel (15 g). This material was dry loaded onto a silica gelcolumn (5 cm×10 cm, 230-400 mesh) with 1:10 methanol:dichloromethane.The main product came off the column as a white solid (0.22 g, 0.62mmol, 54%) m.p. 238-240° C.; [a]²⁰ _(D) =(-) 15.2 (c=0.5 DMF).

Anal. Calcd. for C₁₃ H₁₅ N₃ O₄ Cl₂. 1/2 CH₄ O: C, 44.52; H, 4.70; N,11.54. Found: C, 44.43; H, 4.58; N, 11.36.

EXAMPLE 345,6-Dichloro-2-(ethylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Ethylamine hydrochloride (3.7 g, 46 mmol), triethylamine (7 mL), and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.60 g, 1.1 mmol) were combined with absolute ethanol (20 mL) andstirred at 80° C. for 24 h. The reaction mixture was separated betweensaturated sodium bicarbonate (2×50 mL) and ethyl acetate (200 mL). Theorganics were dried with sodium sulfate, concentrated, and purified on asilica gel column (2.5×18 cm, 230-400 mesh) with 1:20methanol:dichloromethane. The main product off the column was a whitesolid (0.30 g, 0.96 mmol, 87%) m.p. 155-157° C.; [a]²⁰ _(D) =(-) 20.6(c=0.5 DMF).

Anal. Calcd. for C₁₄ H₁₇ N₃ O₄ Cl₂. 1/2 H₂ O: C, 45.30; H, 4.89; N,11.32. Found: C, 45.44; H, 4.78; N, 11.18.

EXAMPLE 352-Cyclopropylamino-5,6-dichloro-1-(alpha-L-ribofuranosyl)-1H-benzimidazole

Cyclopropylamine (10 mL) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-alpha-L-ribofuranosyl)-1H-benzimidazole(0.60 g, 1.1 mmol) (obtained as a minor product from the synthesis ofthe beta anomer, see Example 1) were combined with absolute ethanol (50mL) and stirred at 80° C. for 24 h. The reaction mixture wasconcentrated and purified on a silica gel column (2.5×16 cm, 230-400mesh) with 1:9 methanol:dichloromethane to give 0.25 g of crude product.This material was further purified by multiple cycles on a chromatotron,fitted with a 1 mm silica gel rotor, with 1:15 methanol: dichloromethaneto give a white solid (0.060 g, 0.14 mmol, 14%); m.p. 140-141° C.; [a]²⁰_(D) =(-) 51.8 (c=0.5 DMF); UV l_(max) (e): pH 7.0: 303 nm (10,600), 274(1,700); 0.1 N NaOH: 304 nm (10,800), 275 (2,400); MS (CI): m/z (rel.intensity) 374 (29.7, M+1); ¹ H NMR (DMSO-d₆) d 7.48 (s, 1H, Ar--H),7.38 (s, 1H, Ar--H), 7.08 (br. s, 1H, NH), 5.86 (d, 1H, H-1', J=3.4 Hz),5.50 (d, 1H, OH, J=4.5 Hz), 5.22 (d, 1H, OH, J=7.1 Hz), 4.84 (t, 1H, OH,J=5.7 Hz), 4.15 (dd, 1H, H-2', J=7.9 Hz, J=4 Hz), 7.9 Hz, J=4 Hz), 4.10(dd, 1H, H-3', J=7.3 Hz, J=4.5 Hz), 4.05-4.01 (m, 1H, H-4'), 3.66-3.61(m, 1H, H-5'), 3.47-3.41 (m, 1H, H-5"), 2.74-2.71 (dd, 1H,cyclopropyl-CH, J=6.7 Hz, J=3.3 Hz), 0.69 (d, 2H, J=6.9 Hz,cyclopropyl-CH₂), 0.51-0.45 (m, 2H, cyclopropyl-CH₂).

Anal. Calcd. for C₁₅ H₁₇ N₃ O₄ Cl₂. 0.60 CH₄ O. 0.2 CH₂ Cl₂ : C, 46.24;H, 4.86; N, 10.24. Found: C, 46.13; H, 4.83; N, 10.28.

EXAMPLE 365,6-Dichloro-2-(isopropylamino)-1-(alpha-L-ribofuranosyl)-1H-benzimidazole

Isopropylamine (10 mL ) and2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-alpha-L-ribofuranosyl)-1H-benzimidazole(0.60 g, 1.14 mmol) (obtained as a minor product from the synthesis ofthe beta anomer) were combined with absolute ethanol (10 mL) and stirredat 80° C. for 24 h. The reaction mixture was concentrated and purifiedon a silica gel column (2.5×18 cm, 230-400 mesh) with 1:15methanol:dichloromethane to give 0.39 g of crude product. This materialwas further purified on a chromatotron, fitted with a 1 mm silica gelrotor, with 1:2 acetone: dichloromethane to give a white solid (0.29 g,0.78 mmol, 68%); m.p. 131-133° C.; [a]²⁰ _(D) =(-) 41.4 (c=0.5 DMF); UVl_(max) (e): pH 7.0: 304 nm (11,000), 276 (2,000); 0.1 N NaOH: 306 nm(11,500), 277 (2,500); MS (CI): m/z (rel. intensity) 376 (34.8, M+1); ¹H NMR (DMSO-d₆) d 7.46 (s, 1H, Ar--H), 7.31 (s, 1H, Ar--H), 6.63 (d, 1H,NH, J=7.4 Hz), 5.94 (d, 1H, H-1', J=3.4 Hz), 5.53 (d, 1H, OH, J=4.4 Hz),5.22 (d, 1H, OH, J=7.1 Hz), 4.86 (t, 1H, OH, J=5.7 Hz), 4.15 (dd, 1H,H-2', J=7.7 Hz, J=4.0 Hz), 4.10 (dd, 1H, H-3', J=7.3 Hz, J=4.3 Hz),4.05-3.94 (m, 2H, isopropyl CH, H-4'), 3.69-3.63 (m, 1H, H-5'),3.49-3.41 (m, 1H, H-5"), 1.19 (d, 3H, J=6.5 Hz, isopropyl-CH₃), 1.18 (m,3H, isopropyl-CH₃).

Anal. Calcd. for C₁₅ H₁₇ N₃ O₄ Cl₂. 0.4 CH₂ Cl₂ : C, 45.09; H, 4.86; N,10.24. Found: C, 45.10; H. 4.97; N, 10.00.

EXAMPLE 375,6-Dichloro-2-((2-fluoro-1-methylethylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

Sodium carbonate (0.032 g, 0.30 mmol) and5,6-dichloro-2-(2-fluoroisopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.10 g, 0.20 mmol) were combined with water (1 mL), methanol (2.5 mL)and ethanol (2.5 mL) and stirred at rt for 3 h. The solution wasconcentrated to remove most of the methanol and ethanol and thencombined with ethyl acetate (75 mL). This solution was extracted withsat'd NaCl (2×5 mL). The organics were dried (Na₂ SO₄), decanted, andconcentrated. Purification of the residue on a chromatrotron, fittedwith a 1 mm rotor, with 1:10 methanol : CH₂ Cl₂ gave a white solid(0.066 g, 0.17 mmol, 84%); [a]²⁰ _(D) =(-) 24.8 (c=0.5 DMF); MS (AP+):m/z (rel. intensity) 394 (98, M⁺); ¹ H NMR (DMSO-d₆) d 7.64(s, 1H,Ar--H), 7.37 (s, 1H, Ar--H), 7.13 (d, 0.5H, NH, J=7.9 Hz), 7.07 (d,0.5H, NH, J=7.6 Hz), 5.76 (d, 1H, J=7.9 Hz, H-1'), 5.69 (m, 1H, OH),5.31-5.23 (m, 2H, OH), 4.51-4.45 (m, 1H, CH₂ F), 4.35-4.32 (m, 1H, CH₂F), 4.29-4.17 (m, 2H, H-2' and H-3'), 4.06-3.97 (m, 1H, NHCH), 3.97 (br.s, 1H, H-4'), 3.70-3.31 (m, 2H, H-5'), 1.22-1.18 (m, 3H, CH(CH₃)).

Anal. Calcd. for C₁₅ H₁₈ N₃ O₄ Cl₂ F. 0.40 H₂ O: C, 44.88; H, 4.72; N,10.47. Found: C, 44.98; H, 4.76; N, 10.46.

EXAMPLE 385,6-Dichloro-2-((2-fluoro-1-methylethylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

Fluoroacetone (5 g) and5,6-dichloro-2-amino-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(0.38 g, 0.82 mmol) were combined with tosic acid (0.050 g, 0.26 mmol)and stirred at reflux in a flask fitted with a Dean Stark trap. Afterfour hours sodium cyanoborohydride (0.16 g, 2.4 mmol) was added andreflux was continued for six hours. The solution was diluted with ethylacetate (200 mL) and washed with sat'd NaCl (2×50 mL) and water (50 mL).The organics were dried (Na₂ SO₄), decanted, and concentrated. The crudeproduct was purified on a silica gel column (230-400 mesh, 2.5×18 cm)with 1:25 methanol: CH₂ Cl₂ gave 0.19 g of crude product. This materialwas further purified on a chromatotron (2 mm rotor) with 1:1 ethylacetate hexanes to give a light yellow solid (0.10 g, 0.20 mmol, 24%);MS (API+; m/z (rel. intensity) 520 (62.63, M+); ¹ H NMR (DMSO-d₆) d7.66(s, 1H, Ar--H), 7.51 (s, 1H, Ar--H), 7.30 (d, 1H, NH, J=7.6 Hz),6.25 (d, 1H, H-1', J=7.5 Hz), 5.31-5.23 (m, 1H, H-2'), 5.48-5.44 (m, 1H,H-3'), 4.63-4.26 (m, 6H, CH₂ F, CH, H-4' and 5'), 2.21 (s, 3H, OAc),2.19 (s, 3H, OAc), 2.02 (s,3H, OAc), 1.24 (d, 3H, CH(CH₃), J=7.5 Hz).

Anal. Calcd. for C₂₁ H₂₄ N₃ O₇ Cl₂ F: C, 48.47; H, 4.65; N, 8.08. Found:C, 48.60; H, 4.73; N, 7.94.

EXAMPLE 39 5,6-Dichloro-2-(isopropylamino)-1H-benzimidazole

5,6-Dichloro-1,2-phenylenediamine (0.61 g, 3.4 mmol), and isopropylisothiocyanate (0.39 g, 3.8 mmol) were combined in anhydrous pyridine(10 mL) and were heated to 80° C. for 15 min. Dicyclohexylcarbodiimide(1.06 g, 5.14 mmol) was then added and the resulting mixture was allowedto stir at 100° C. for 5 h. Toluene (30 mL) was added and the mixturewas concentrated by rotary evaporation leaving a brown residue. Theproduct was further purified by silica gel chromatography using6.5:3:0.5 ethyl acetate/hexane/triethylamine to afford a gummy solidwhich was recrystallised from acetonitrile to give 0.46 g (60%) of a tansolid; m.p. 218-220° C. Anal. Calcd for C₁₀ H₁₁ Cl₂ N₃ : C, 49.20; H,4.54; N, 17.21. Found: C, 49.31; H, 4.59; N, 17.33.

General Procedure I

Synthesis of 2-(alkylamino)-1H-benzimidazoles Using1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulphonateas Desulphurising Agent.

The appropriate 1,2-phenylenediamine is combined with the appropriateisothiocyanate (1.0-1.25 mmol/mmol of diamine) and anhydrous pyridine(3-5 mL/mmol of diamine). The resulting mixture is heated to 80° C. for30 min, then 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulfonate (1.1-1.35 mL/mmol of diamine) is added as asolid in one portion. The resulting mixture is allowed to stir at 80-90°C. for 3-20 h, after which time it is allowed to cool to roomtemperature. The remainder of the procedure is the same as detailedabove, except that the product is purified either by silica gelchromatography or by recrystallization from either acetonitrile or1,4-dioxane.

5,6-Dichloro-2-(isopropylamino)-1H-benzimidazole

5,6-Dichloro-1,2-phenylenediamine (200.0 g, 1.13 mol), isopropylisothiocyanate (122.0 g, 1.21 mol),1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate(622.0 g, 1.47 mol) and pyridine (4 L) were used according to generalprocedure I. The product was recrystallized from acetonitrile to give184 g (67%) of a brown solid. Analytical data were consistent with thosereported above.

2-(Cyclopropylamino)-5,6-dichloro-1H-benzimidazole

4,5-Dichloro-1,2-phenylenediamine (6.04 g, 34.1 mmol), cyclopropylisothiocyanate (3.69 g, 37.2 mmol),1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate(20.1 g, 47.4 mmol) and pyridine (135 mL) were used according to generalprocedure I. The product was recrystallized from acetonitrile to afford5.82 g (70%) of a yellow solid; m.p. 223-225° C. Anal. Calcd for C₁₀ H₉Cl₂ N₃ : C, 49.61; H, 3.75; N, 17.36. Found: C, 49.53; H, 3.78; N,17.12.

General Procedure II

Coupling of 2-(alkylamino)-1H-benzimidazole with1,2,3,5-tri-O-acetyl-L-ribofuranose

The appropriate 2-(alkylamino)-1H-benzimidazole was combined with1,2-dichloroethane (2-3 mL/mmol of benzimidazole) andN,O-bis(trimethylsilyl)acetamide (1-1.25 mmol/mmol of benzimidazole) andthe resulting mixture was heated to 80° C. for 30 min. Trimethylsilyltrifluoromethanesulfonate (0.5-0.7 mmol/mmol of benzimidazole) was addedand the mixture was allowed to stir at 80° C. for an additional 15 min,after which time 1,2,3,5-tetra-O-acetyl-L-ribofuranose (1-1.25 mmol/mmolof benzimidazole) was added as a solid in one portion. The resultingmixture was allowed to stir at 80° C. for 2-20 h, after which time itwas allowed to cool to room temperature. It was then diluted with 5%aqueous sodium bicarbonate (10 mL/mmol of benzimidazole) anddichloromethane (3-5 mL/mmol of benzimidazole) and the two-phase mixturewas stirred at room temperature for 30 min. The organic layer wascollected and the aqueous layer was back-extracted with an additionalportion of dichloromethane (3-5 mL/mmol of benzimidazole) and thecombined organic layers were dried over magnesium sulfate, filtered andthe solvents were removed under reduced pressure using a rotaryevaporator. The products were further purified by silica gelchromatography.

5,6-Dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

5,6-Dichloro-2-(isopropylamino)-1H-benzimidazole (25.0 g, 102 mmol),N,O-bis(trimethylsilyl)acetamide (25.9 mL, 21.3 g, 105 mmol, 1.03 eq.),1,2-dichloroethane (300 mL), trimethylsilyl trifluoromethanesulfonate(12.8 mL, 14.7 g, 66.2 mmol, 0.65 eq.) and1,2,3,5-tri-O-acetyl-L-ribofuranose (34.1 g, 107 mmol, 1.05 eq.) wereused according to general procedure II. Silica gel chromatography using35:1 dichloromethane/methanol afforded 39.6 g (77%) of a yellow foam. MS(CI): m/z 501 (M+1).

General Procedure III

Deprotection of2-(alkylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole

The appropriate2-(alkylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazolewas dissolved in ethanol (4-5 mL/mmol of triacetate). Into a separateflask were placed sodium carbonate (1.0-1.3 mmol/mmol of triacetate),water (1-2 mL/mmol of triacetate), and methanol (3 mL/mmol oftriacetate). The sodium carbonate suspension was added to the ethanolicsolution of the triacetate at room temperature and in one portion. Theresulting mixture was allowed to stir at room temperature for 18 h. Themixture was then diluted with ethyl acetate (25 mL/mmol of triacetate).The organic layer was collected and was washed with saturated aqueousbrine (100 mL/mmol of triacetate), dried over magnesium sulfate.filtered, and the solvents were removed by rotary evaporation. Theproducts were further purified by silica gel chromatography.

5,6-Dichloro-2-(isopropylamino)-1-(beta-L-ribofuranosyl)-1H-benzimidazole

5,6-Dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole(7.50 g, 14.93 mmol), sodium carbonate (1.72 g, 16.23 mmol), water (29mL), methanol (100 mL) and ethanol (100 mL) were used according togeneral procedure III. The product was purified by silica gelchromatography using 55:45 dichloromethanelmethanol to afford 4.72 g(84%) of a white foam. Analytical data were consistent with the assignedstructure.

EXAMPLE 40 Human Cytomegalovirus (HCMV) Assay

HCMV strain AD169 was grown on monolayers of human embryonic lung cells(MRC₅ cells) in 96 well plates. After infection of the cells at a ratioof approximately 0.01 infectious virus particles per cell, the compoundsto be tested were added to selected wells at six differentconcentrations, each in triplicate. The same concentrations of compoundwere also applied to wells containing monolayers of uninfected cells inorder to assess compound cytotoxicity. The plates were incubated for 5days, and the minimum cytotoxic dose was estimated from microscopicexamination. The IC₅₀ for antiviral effect was estimated frommeasurements of HCMV DNA in each well by blotting and quantitivespecific DNA hybridization, similar to the method of Gadler.(Antimicrob. Agents Chemother. 1983, 24, 370-374).

    ______________________________________                                                       HCMV       MRC5 tox                                            Example        IC50                CC50                                       ______________________________________                                         Example 3     0.06-0.23 μM                                                                           30 μ M                                          Example 4           0.91-2.5 μM                                                                         100 μM                                        Example 5           0.03-0.05 μM                                                                       100 μM                                         Example 10         1.1-1.3 μM                                                                            100 μM                                       Example 8            41 μM                                                                                       100 μM                               Example 12        3.5-5.8 μM                                                                             100 μM                                       Example 34         0.75-0.85 μM                                                                        100 μM                                         ______________________________________                                    

EXAMPLE 41 Tablet Formulations

The following formulations A and B were prepared by wet granulation ofthe ingredients with a solution of povidone, followed by addition ofmagnesium stearate and compression.

    ______________________________________                                         Formulation A                                                                                 mg/tablet                                                                            mg/tab1et                                             ______________________________________                                         (a) Active ingredient                                                                           250      250                                               (b) Lactose B.P.                           26                                 (c) Povidone B.P.                           9                                 (d) Sodium Starch Glycollate                                                                              20                                                                                           12                                 (e) Magnesium Stearate                                                                                5          3                                                                                   300       500                        ______________________________________                                    

    ______________________________________                                        Fomulation B                                                                                   mg/tablet                                                                            mg/tablet                                             ______________________________________                                          (a) Active ingredient                                                                          250      250                                               (b) Lactose                   --          150                                 (c) Avicel PH 101                          26                                 (d) Povidone B.P.                           9                                 (e) Sodium Starch Glycollate                                                                             20                                                                                            12                                 (f) Magnesium Stearate                                                                                5          3                                                                                   300         500                      ______________________________________                                    

    ______________________________________                                        Formulation C                                                                                mg/tablet                                                      ______________________________________                                         Active ingredient                                                                             100                                                          Lactose                                           200                         Starch                                               50                       Povidone                 5                                                    Magnesium sterate                                                                                                     359                                   ______________________________________                                    

The following formulations, D and E, were prepared by direct compressionof the admixed ingredients. The loctose used in formulation E was of thedirect compression type (Dairy Crest--"Zeparox").

    ______________________________________                                         Formulation D                                                                                 mg/tablet                                                    ______________________________________                                         Active Ingredient 250                                                        Pregelatinised Starch NF15                                                                         150                                                                             400                                                    ______________________________________                                    

    ______________________________________                                        Formulation E                                                                               mg/tablet                                                       ______________________________________                                        Active Ingredient                                                                             250                                                           Lactose                                               150                     Avicel                     100                                                ______________________________________                                                        500                                                       

Formulation F (Controlled Release Formulation)

The formulation was prepared by wet granulation of the ingredients(below) with a solution of povidone followed by the addition ofmagnesium stearate and compression.

    ______________________________________                                                                                               mg/tablet              ______________________________________                                          (a) Active Ingredient                                                                            500                                                      (b) Hydroxypropylmethylcellulose                                                                                112                                         (Methocel K4M Premium)                                                        (c) Lactose B.P.                                    53                        (d) Povidone B.P.C.                              28                           (e) Magnesium Stearate                                                                                       7                                                                   700                                                      ______________________________________                                    

EXAMPLE 42 Capsule Formulations

Formulation A

A capsule formulation was prepared by admixing the ingredients ofFormulation D in Example 1 above and filling into a two-part hardgelatin capsule. Formulation B (infra) was prepared in a similar manner.

    ______________________________________                                        Formulation B                                                                                  mg/tablet                                                    ______________________________________                                        (a) Active ingredient                                                                            250                                                        (b) Lactose B.P.                                143                           (c) Sodium Starch Glycollate                                                                                         25                                     (d) Magnesium Stearate                                                                                     2                                                ______________________________________                                                           420                                                    

    ______________________________________                                        Formulation C                                                                                mg/tablet                                                      ______________________________________                                         (a) Active ingredient                                                                         250                                                          (b) Macrogol 4000 BP                                                                              350                                                       ______________________________________                                                         600                                                      

Capsules were prepared by melting the macrogol 4000 BP, dispersing theactive ingredient in the melt and filling the melt into a two-part hardgelatin capsule.

    ______________________________________                                         Formulation D                                                                              mg/tablet                                                       ______________________________________                                          Active ingredient                                                                           250                                                           Lecithin                                               100                    Arachis Oil             100                                                   ______________________________________                                                        450                                                       

Capsules were prepared by dispersing the active ingredient in thelecithin and arachis oil and filling the dispersion into soft, elasticgelatin capsules.

Formulation E (Controlled Release Capsuler)

The following controlled release capsule formulation was prepared byextruding ingredients a, b and c using an extruder, followed byspheronisation of the extrudate and drying. The dried pellets were thencoated with release-controlling membrane (d) and filled into atwo-piece, hard gelatin capsule.

    ______________________________________                                                          mg/tablet                                                   ______________________________________                                         (a) Active Ingredient                                                                            250                                                       (b) Microcrystalline Cellulose                                                                                       125                                    (c) Lactose BP                                         125                    (d) Ethyl Cellulose      13                                                                       513                                                       ______________________________________                                    

EXAMPLE 43 Injectable Formulation

    ______________________________________                                         Formulation A                                                                ______________________________________                                        Active ingredient    0.200 g                                                  Hydrochloric acid solution, 0.1 M                                                                                    q.s. to pH 4.0 to 7.0                  Sodium hydroxide Solution, 0.1 M                                                                                      q.s. to pH 4.0 to 7.0                 Sterile water                                             q.s. to 10          ______________________________________                                                             ml                                                   

The active ingredient was dissolved in most of the water (35°-40° C.)and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid orthe sodium hydroxide as appropriate. The batch was then made up tovolume with the water and filtered through a sterile micropore filterinto a sterile 10 ml amber glass vial (type 1) and sealed with sterileclosures and overseals.

    ______________________________________                                         Formulation B                                                                ______________________________________                                         Active ingredient       0.125 g                                              Sterile, pyrogen-free, pH7 phosphate buffer,                                                                     q.s. to 25 ml                              ______________________________________                                    

EXAMPLE 44

    ______________________________________                                         Intramuscular injection                                                      ______________________________________                                         Active ingredient    0.20 g                                                  Benzyl Alcohol                                           0.10 g               Glycofurol                                                  1.45 g            Water for Injection                                q.s. to 3.00               ______________________________________                                                              ml                                                  

The active ingredient was dissolved in the glycofurol. The benzylalcohol was then added and dissolved, and water added to 3 ml. Themixture was then filtered through a sterile micropore filter and sealedin sterile 3 ml amber glass vials (type 1).

EXAMPLE 45

    ______________________________________                                        Syrup                                                                         ______________________________________                                         Active ingredient   0.2500 g                                                 Sorbitol Solution                                       1.5000 g              Glycerol                                                         2.0000                            g                                                        Sodium Benzoate                                           0.0050 g            Flavour, Peach 17.42.3169                                                                                                  0.0125 ml                        Purified Water                                             q.s. to 5.0000                          ml                                                       ______________________________________                                    

The active ingredient was dissolved in a mixture of the glycerol andmost of the purified water. An aqueous solution of the sodium benzoatewas then added to the solution, followed by addition of the sorbitolsolution and finally the flavour. The volume was made up with purifiedwater and mixed well.

EXAMPLE 46

    ______________________________________                                         Suppository                                                                                        mg/suppository                                          ______________________________________                                          Active Ingredient (63 lm)*                                                                           250                                                  Hard Fat, BP (Witepsol H15 - Dynamit Nobel)                                                                  1770                                                                                     2020                                ______________________________________                                    

One-fifth of the Witepsol H15 was melted in a steam-jacketed pan at 45°C. maximum. The active ingredient was sifted through a 1001 m sieve andadded to the molten base with mixing, using a silverson fitted with acutting head, until a smooth dispersion was achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 was added to thesuspension and stirred to ensure a homogeneous mix. The entiresuspension was passed through a 2501 m stainless steel screen and, withcontinuous stirring, was allowed to cool to 40° C. At a temperature of38° C. to 40° C., 2.02 g of the mixture was filled into suitable, 2 mlplastic moulds. The suppositories were allowed to cool to roomtemperature.

EXAMPLE 47

    ______________________________________                                        Pessaries                                                                                     mg/pessary                                                    ______________________________________                                         Active ingredient (631 m)                                                                      250                                                         Anhydrate Dextrose                                                                                                              380                         Potato Starch                                          363                    Magnesium Stearate                                                                                7                                                                           1000                                                        ______________________________________                                    

The above ingredients were mixed directly and pessaries prepared bydirect compression of the resulting mixture.

We claim:
 1. A compound of formula (I) ##STR10## wherein R representshydrogen, a halo atom, --NR¹ R² where R¹ and R², which may be the sameor different, are each independently selected from hydrogen, C₁₋₆ alkyl,cyanoC₁₋₆ alkyl, hydroxyC₁₋₆ alkyl, haloC₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₁₋₆ alkylC₃₋₇ cycloalkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkylC₁₋₆ alkyl, C₂₋₆alkynyl, aryl, arylC₁₋₆ alkyl, heterocyclicC₁₋₆ alkyl, --COC₁₋₆ alkyl orR¹ and R² together with the N atom to which they are attached form a 3,4, 5 or 6 membered heterocyclic ring or a pharmaceutically acceptablederivatives thereof.
 2. A compound according to claim 1, in the form ofa β-anomer.
 3. A compound according to claim 1, in the form of anα-anomer. 4.5,6-dichloro-2-isopropylamino-1-(β-L-ribofaranosyl)-1H-benzimidazole. 5.A compound according to claim 1 wherein R represents --NR¹ R² wherein R¹represents hydrogen and R² is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyland haloC₁₋₆ alkyl or a pharmaceutically acceptable derivatives thereof.6. A compound according to claim 1 wherein R represents isopropylamino,isobutylamino, sec-butylamino, cyclopropylamino, cyclopentylamino or2-fluoro-1-methylethylamino or a pharmaceutically acceptable derivativesthereof.
 7. A compound according to claim 1 selected from5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole,2-cyclopropylamino-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazoleand5,6-dichloro-2-((2-fluoro-1-methyl-ethylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoleor a pharmaceutically acceptable derivative thereof.
 8. A compound offormula (II) ##STR11## wherein L is hydrogen or a suitable leaving atomor group and R³, R⁴ and R⁵ are each a hydroxy or a protected hydroxygroup.
 9. A compound according to claim 4 wherein L is hydrogen or ahalo atom and R³, R⁴ and R⁵ are each a hydroxy or a protected hydroxygroup.
 10. A compound according to claim 9 wherein R³, R⁴, and R⁵ areeach OC(O)CH₃. 11.2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1H-benzimidazole.12. 2-bromo-5,6-dichloro-1-(β-L-ribofuranosyl)-1H-benzimidazole.
 13. Acompound of formula (Ib) ##STR12## wherein R represents a halo atom or--NR¹ R² wherein R¹ represents hydrogen and R² is selected from C₁₋₆alkyl, hydroxyC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkylC₃₋₇ cylcoalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, arylalkyl, or R¹ and R², which may bethe same or different, are both C₁₋₆ alkyl, or R¹ and R² together withthe N atom to which they are attached form a 3, 4, 5, or 6 memberedheterocyclic ring or a pharmaceutically acceptable derivative thereof.14. A pharmaceutical formulation comprising a compound of formula (I) asdefined in claim 1 or a pharmaceutically acceptable derivative thereof,together with pharmaceutically acceptable carrier therefore.
 15. Apharmaceutically acceptable derivative of a compound according toclaim
 1. 16. A derivative according to claim 15 in the form of a salt.17. A derivative according to claim 15 in the form of an ester.
 18. Aderivative according to claim 16 wherein the salt is selected from saltsof organic carboxylic acids, organic sulphonic acids and inorganicacids.
 19. A derivative according to claim 17 wherein the ester isselected from carboxylic acid, sulphonate, amino acid, phosphonate andmono-, di- or tri-phosphate esters.
 20. A pharmaceutical compositioncomprising an effective antiviral amount of the compound5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole ora pharmaceutically acceptable derivative thereof and a pharmaceuticallyacceptable carrier therefor.
 21. A pharmaceutical composition accordingto claim 20 in the form of a tablet or capsule.
 22. A pharmaceuticalcomposition according to claim 21 wherein the tablet or capsule contains5 to 1000 mg of5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole ora pharmaceutically acceptable derivative thereof.
 23. A pharmaceuticalcomposition according to claim 20 in the form of a solution orsuspension.
 24. A method of treatment of a herpes virus infection in aninfected animal which comprises treating said animal with atherapeutically effective amount of a compound as defined according toclaim
 1. 25. A method according to claim 24 wherein the herpes virusinfection is selected from herpes simplex virus 1, herpes simplex virus2, varicella zoster virus, cytomegalovirus (CMV), Epstein Barr virus,human herpes virus 6 and human herpes virus
 7. 26. A method of treatmentof a herpes virus infection in a human comprising administration to saidhuman of an effective herpes virus infection treatment amount of thecompound5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole.27. The method of claim 26 wherein the herpes virus infection is CMV orEpstein Barr virus infection.
 28. The method according to claim 26wherein the administration of5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole isby an intravenous or intravitreal route.
 29. A method of preventing thesymptoms or effects of a CMV infection in a human comprisingadministering to said human an effective amount of the compound5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole.30. A method of treatment of a CMV infection in a human, comprisingadministering to said human an effective CMV treatment amount of5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole ora pharmaceutically acceptable salt or ester thereof.